The insertion of a nitrene (NR) into a C—H bond is a transformation with great synthetic promise. The conversion of a C—H bond into an amine offers a way to introduce a N-atom into an organic molecule. Since most organic molecules contain C—H bonds, such a method would allow for the insertion of a NR group into many organic molecules. More traditional means of adding a N atom into an organic molecule generally require the presence of a functional group such as a C—X (X=halogen, pseudohalogen, or OR) or the presence of a double bond (C═O, or C═C-hydroamination). See Godula, K. and Sames, D. (2006) Science, 312:67-72; Cenini et al (2006) Coord. Chem. Rev., 250:1234-1253; Halfen, J. A. (2005) Curr. Org. Chem., 9:657-669; Davies, H. M. L. and Long, M. S. (2005) Angew. Chem. Int. Ed., 44:3518-3520; Müller, P. and Fruit, C. (2003) Chem. Rev., 103:2905-2919.
Transition metal-catalyzed C—H bond amination generally involves generation of a nitrene (NR) in the presence of a transition metal catalyst [M] which is thought to stabilize it against the generally non-selective reactivity of free nitrenes (Davies and Long, Ibid.) This transition metal-stabilized nitrene [M]=NR or [M]2(μ-NR) then undergoes further reaction with an organic substrate more selectively than the free nitrene.
Two main modes of reactivity have been observed for transition metal catalyzed reactions of nitrenes. Addition to unsaturated organic molecules such as alkenes may be observed, giving rise to aziridines. This produces a valuable family of strained, three-membered rings containing one N atom, which appear in biologically active compounds and also serve as versatile synthetic intermediates to more complex structures owing to facile ring opening by a variety of nucleophiles. A competing mode of reactivity is insertion into C—H bonds. The factors that control this selectivity are not entirely clear, and some catalysts that serve as effective aziridination catalysts also perform catalytic C—H amination (Scheme 1).

Ru-porphyrin complexes such as that depicted in Formula I have been used to perform intermolecular catalytic amination of C—H bonds with sulfonylnitrene precursors such as PhI═NTs. Discrete [Ru]=NTs and [Ru](═NTs)2 species have been isolated, and shown to react with olefins to give aziridines or C—H bonds to give amines, and it has been shown that the rate depends on the strength of the C—H bond being activated, with weaker C—H bonds undergoing faster amination. See Leung et al. (2005) JACS, 127:16629-16640; Au et al. (1999) JACS, 121:9120-9132.

A copper-based system with brominated tris(pyrazolyl)borate ligands has also shown significant activity in intermolecular C—H amination reactions (Scheme 2). See Fructos et al. (2006) JACS, 128:11784-11791; Díaz-Requejo et al. (2003) JACS, 125:12078-12079. It is also a very good aziridination catalyst with many olefins to give N-tosylaziridines. See Díaz-Requejo et al. (1997) Organometallics, 16:4399-4402; Díaz-Requejo et al. (2001) J. Organomet. Chem., 617-618:110-118; Mairena et al. (2004) Organometallics, 23:253-256. Since rates of C—H amination are controlled by the strength of the C—H bonds, benzylic and substituted benzylic C—H bonds serve as efficient reaction partners with PhI═NTs. What is significant is the reasonable yield with cyclohexane, a substrate containing only secondary C—H bonds. Amidation of aromatic C—H bonds is also possible. Reaction of PhI═NTs with benzene gives PhNHTs in 80% yield. Electron-poor phenanthroline ligands in conjunction with Cu(I) salts allows for the tosylamination of electron-rich phenyl rings such as 1,3-(MeO)2C6H4 in 63% yield. See Hamilton et al. (2004) Chem. Commun., 1628-1629.

However, there are a number of limitations associated with these methodologies. For example, (1) they often require the use of tosyl imides, or electron-poor N-substituents; and (2) the PhI═NTs or NaNTsCl precursors must be isolated before use, the later of which is commercially available (See Fructos, supra).
More recent advances describe the in situ generation of an iminoiodane PhI═NR for use in transition metal catalyzed C—H nitrene insertion by reaction of a amine H2NR bearing very electron withdrawing —SO2R, C(O)OR, or C(O)CF3 substituents R. See Davies (supra); Dodd, R. H., and Daubon, P. (2003) Synlett., 11. This has been exploited for a powerful intramolecular variant of the C—H bond amination reaction leading to the formation of 5- and 6-membered N-containing heterocycles. One of the key features of this reaction is that C—H bond insertion proceeds with retention of configuration. See Davies (Ibid.); Liang et al. (2006) Angew. Chem. Int. Ed., 45:4641-4644; Du Bois, J. and Hinman, A. (2003) JACS, 125:11510-11511; Espino, C. G. and Du Bois, J. (2001) Angew. Chem. Int. Ed., 40:598-600. This is typical behavior of singlet nitrenes, but not triplet nitrenes, which generally participate in H-atom abstraction reactions to generate radical species. For instance, Espinso et al. (Ibid.) demonstrated that the cyclization of an enantiopure carbamate results in the formation of enantiomerically pure oxazolidinone, wherein one product was observed by chiral GC (Scheme 3).

A chiral amination catalyst such as a Ru(II) tetraaryl porphyrin with four chiral auxiliaries on the four aryl rings opened the possibility to inducing enantioselectivity with pro-chiral substrates. See Liang et al. (2004) J. Org. Chem., 69:3610-3619; Liang et al. (2002) Angew. Chem. Int. Ed., 41:3465-3468. For example, when sulfamate esters H2NSO3R were employed, respectable enantioselectivities were observed (Scheme 4)

The use of organoazides RN3 could considerably expand the range of amine products that could be obtained through catalytic amination. A cobalt porphyrin system has been reported to aminate toluene and other substrates with benzylic C—H bonds. See Cenini (supra); Caselli et al. (2005) J. Organometal. Chem., 690; Fantauzzi et al. (2005) Organometallics, 24:4710-4713; Cenini et al. (1999) J. Mol. Catal. A, 137:135-146; Cenini et al. (2000) Chem. Commun., 2265-2266; Ragaini et al (2003) Chem. Eur. J., 9:249-259. Use of p-substituted arylazides X—C6H4N3 (X═NO2, OMe, Cl, H, Me, F, Br, CN) gives rise to the corresponding imine p-XC6H4N═CHPh in 6-38%, whilst amine p-XC6H4NH2 and diazine p-XC6H4N═NC6H4X account for remainder of arylazide (Scheme 5).

Substrates with a weaker C—H bond than that of the benzylic position of toluene such as cyclohexene result in the formation of a secondary amine as the predominant product (Scheme 6). For this mode of reactivity, it appears that electron-withdrawing substituents on the aryl ring increase the selectivity towards C—H bond amination.
